Results

Demography

Of the 225 UK Caucasian myositis patients recruited, 117 had PM (81 females, 69.2%), and 108 DM (75 females, 69.4%) (Table1), confirming the expectedfemalepredominance in both myositis subtypes. As shown, the mean age at onset of myositis was similar for PM and DM, at 50.4 versus 49 years, respectively. The medianduration of disease at data capture was three years for PM and DM. A similar proportion of patients in each group had ILD (PM = 15.4%, DM = 17.6%). The presence of malignancy was observed in an increased proportion of DM (13.0%) compared to PM (1.7%) patients.

Table 1

n (%)

Polymyositis

Dermatomyositis

(n = 117)

(n = 108)

Females

81 (69.2)

75 (69.4)

Average age of onseta

50.4 ± 14.5

49.0 ± 14.1

Interstitial lung disease

18 (15.4)

19 (17.6)

Malignancyb

2 (1.7)

14 (13.0)

Antibody status

(n = 105)

(n = 101)

Myositis-specific antibodies

Jo-1

24 (22.9)

22 (21.8)

PL-7

1 (1.0)

0

PL-12

0

1 (1.0)

EJ

0

1 (1.0)

OJ

1 (1.0)

1 (1.0)

KS

1 (1.0)

1 (1.0)

Any of the abovec

27 (25.7)

25 (24.7)

Mi-2d

1 (1.0)

17 (16.8)

SRP

5 (4.8)

2 (2.0)

Myositis-associated antibodies

U1-RNP

5 (4.8)

8 (7.9)

U3-RNP

0

2 (2.0)

Ku

0

2 (2.0)

PM-Scl

5 (4.8)

6 (5.9)

None of the above autoantibodies

62 (59.1)

45 (44.5)

Patient details and antibody frequencies

Overall allelic results

There were large and highlysignificant differences in overall allelic distributions between PM and controls for the HLA-DRB1 and DQA1 loci (Table 2; p = 0.0001). Significant but weaker association was observed between DM and controls at HLA-DRB1 (p = 0.009) and DQA1 (p = 0.02), but the HLA-DQB1 distribution was more significant in DM (p = 0.008) than in PM (p = 0.02). These associations were largelyaccounted for by differences versus controls at the specific alleles: HLA-DRB1*03, DQA1*05 and DQB1*02. In light of this, a 'relative predispositional effect' test was performed to examine whether the effect of other alleles had been masked by the relatively increased frequency of these alleles [21]. HLA-DRB1*03, DQA1*05 and DQB1*02 were therefore removed from the data, and the overall exact testsrecalculated, after which no further overall differences were detected between myositis subtype versus controls. When PM was compared directly with DM, significant overall differences were observed at both HLA-DRB1 (p = 0.004) and DQA1 (p = 8 × 10-5).

Table 2

HLA

Controls

Polymyositis

Dermatomyositis

n (%)

n (%)

n (%)

DRB1

(n = 537)

(n = 115)

(n = 107)

01

127 (23.6)

25 (21.7)

27 (25.2)

02

145 (27.0)

23 (20.0)

19 (17.8)

03

151 (28.1)

72 (62.6)

50 (46.7)

04

195 (36.3)

31 (27.0)

39 (36.4)

07

129 (24.0)

11 (9.6)

37 (34.6)

08

37 (6.9)

5 (4.3)

2 (1.9)

09

12 (2.2)

1 (0.9)

2 (1.9)

10

8 (1.5)

3 (2.6)

0 (0)

11

61 (11.4)

16 (13.9)

11 (10.3)

12

11 (2.0)

3 (2.6)

1 (0.9)

13

96 (17.9)

18 (15.6)

10 (9.3)

14

30 (5.6)

5 (4.3)

5 (4.7)

p

0.0001

0.009

DQA1

(n = 142)

(n = 110)

(n = 104)

01

92 (64.8)

62 (56.4)

57 (54.8)

02

33 (23.2)

10 (9.1)

36 (34.6)

03

60 (42.3)

31 (28.2)

39 (37.5)

04

5 (3.5)

3 (2.7)

1 (1.0)

05

55 (38.7)

82 (74.5)

58 (55.8)

06

2 (1.4)

2 (1.8)

0 (0)

p

0.0001

0.02

DQB1

(n = 153)

(n = 116)

(n = 108)

02

61 (39.9)

76 (65.5)

71 (65.7)

03

87 (56.9)

56 (48.3)

57 (52.8)

04

9 (5.9)

5 (4.3)

3 (2.8)

05

42 (27.5)

35 (30.2)

32 (29.6)

06

65 (42.5)

37 (31.9)

31 (28.7)

p

0.02

0.008

Frequency of HLA class II phenotypes

HLA associations

As outlined, there were significant increases in the frequencies of HLA-DRB1*03, DQA1*05 and DQB1*02 in PM versus controls (Table 2). In DM versus controls, the frequencies of HLA-DRB1*03 and DQA1*05 were also increased, but to a lesserdegree. The frequency of HLA-DRB1*07 was clearly reduced in PM, both compared to controls and DM. The HLA-DQA1*02 results closelymirrored the DRB1*07 results for PM/DM patients and controls. In PM and to a lesser degree DM, both HLA-DRB1*03 and DQA1*05 demonstrated positive and highly significant associations versus controls (Table 3). HLA-DQB1*02 was a risk factor for PM and DM, with a similar strength of association. HLA-DRB1*07 and DQA1*02 were protective factors for PM and, by contrast, were risk factors for DM. Strong pairwise LD was demonstrated between HLA-DRB1*03, DQA1*05 and DQB1*02, and also between DRB1*07 and DQA1*02 (data not shown, p < 0.00001). Homozygosity for HLA-DQA1*05 was a risk factor for PM (34.9% versus 9.4%, OR 5.2, 95% CI 1.9–14.8, corrected probability (pcorr) = 0.003), but conferring no additional risk over DQA1*05 heterozygotes. No further statistical associations with homozygosity were found.

Table 3

Polymyositis

Dermatomyositis

HLA phenotype

p

pcorr

OR (95% CI)

p

pcorr

OR (95% CI)

DRB1*03

6 × 10-12

7 × 10-11

4.3 (2.8–6.7)

2 × 10-04

0.003

2.2 (1.4–3.5)

DRB1*07

4 × 10-04

0.005

0.3 (0.2–0.6)

0.03

NS

1.7 (1.04–2.6)

DQA1*02

0.004

0.02

0.3 (0.1–0.7)

0.06

NS

1.7 (0.96–3.2)

DQA1*05

1 × 10-08

9 × 10-08

4.6 (2.6–8.3)

0.01

0.06

2.0 (1.2–3.4)

DQB1*02

4 × 10-05

2 × 10-04

2.9 (1.7–4.9)

5 × 10-05

3 × 10-04

2.9 (1.7–5.0)

Results of univariate analyses for disease versus controls

To determine whether there were independent effects in the HLA class II association for PM/DM, a logistic regression modelincorporating HLA-DRB1*03, DQA1*05 and DQB1*02 was investigated. In PM, HLA-DQA1*05 had the strongest effect and there was no additional independent effect of DRB1*03 and DQB1*02. For DM, the strongest risk factor was DQB1*02, after accounting for DQA1*05 and DRB1*03. This was confirmed using forwards and backwards stepwise logistic regression. When DM and PM were directly compared, using logistic regression to allow for all other significant alleles, a highly significant between-subtype difference was found due to HLA-DRB1*07 and DQA1*02 (OR 4.2, 95% CI 1.9–9.3 for both).

Serological subsets

Five DM patients had more than one MSA/MAA, including one with three antibodies (Jo-1, Ku, U1-RNP). In all but one patient (who was Jo-1 and PL-12 positive), the second antibody was anti-U1-RNP. In patients with single MSAs/MAAs, the anti-tRNA synthetase antibodies were the most abundant and detectable in 25% of both PM and DM patients tested (Table 1). Anti-Jo-1 antibody was the most common anti-tRNA synthetase detected. A decreased proportion of patients had negative serology in DM compared to PM (p = 0.05), but this was largely attributable to the excess of anti-Mi-2 antibodies observed in DM (16.8% DM versus 1% PM, OR 21.0, 95% CI 3.1–887.7, p = 2.9 × 10-5). The frequency of anti-SRP antibodies was increased in PM (4.8%) versus DM (2.0%).

In PM/DM combined, HLA-DRB1*03, DQA1*05 and DQB1*02 were all strong risk factors for the presence of anti-tRNA synthetase and anti-PM-Scl antibodies versus controls (Table 4). The associations persisted after stratifying for anti-Jo-1 antibody or myositis subtype. No significant HLA differences were observed between PM and DM in anti-tRNA synthetase positive patients. HLA-DRB1*07, DQA1*02 and DQB1*02 were all strong risk factors in anti-Mi-2-positive patients versus controls. Using logistic regression, HLA-DRB1*07 and DQA1*02 were the main risk factors for the presence of anti-Mi-2 antibodies (data not shown). There were no independent genetic or serological associations observed in the cancer-associated myositis patients (hence these patients were retained in the PM/DM subgroup analysis).

Table 4

HLA phenotype/serology

n (%)

p

pcorr

OR (95% CI)

DRB1*03

Synthetase

44 (84.6)

1 × 10-15

1 × 10-14

14.1 (6.3–35.2)

PM-Scl

11 (100)

3 × 10-6

4 × 10-5

30.6 (4.4–1309.1)

DRB1*07

Mi-2

14 (77.8)

4 × 10-6

5 × 10-5

11.1 (3.4–46.8)

DQA1*02

Mi-2

14 (77.8)

9 × 10-6

5 × 10-5

11.6 (3.3–50.6)

DQA1*05

Synthetase

42 (85.7)

7 × 10-9

4 × 10-8

9.5 (3.8–26.5)

PM-Scl

11 (100)

0.0002

0.001

18.9 (2.6–814.9)

DQB1*02

Synthetase

42 (85.7)

6.6 × 10-9

4 × 10-8

9.5 (3.8–26.5)

Mi-2

15 (83.3)

7 × 10-4

0.004

7.5 (2.0–41.9)

PM-Scl

11 (100)

0.0003

0.001

18.0 (2.5–777.4)

Comparison of HLA class II phenotypes in serological subsetsa

Haplotype frequencies

LD existed between the HLA class II loci, and thus haplotype frequencies were compared in cases and controls (Table 5). As expected, there was an excess of the DRB1*03-DQA1*05-DQB1*02 haplotype in PM/DM combined versus controls. When stratified by IIM subtype, only the PM versus control association was significant after correction for multiple comparisons. The DRB1*03-DQA1*05-DQB1*02 association was even stronger in anti-tRNA synthetase positive patients versus controls. Compared to controls, the DRB1*07-DQA1*02-DQB1*02 haplotype frequency was increased in DM (p = not significant (NS)), but reduced in PM (puncorr = 0.03). The DRB1*07-DQA1*02-DQB1*02 haplotype was a significant risk factor in anti-Mi-2 positive patients versus controls. This haplotype discriminated PM from DM (OR 0.3, 95% CI 0.1–0.6, pcorr = 0.002), even after allowing for the presence of anti-Mi-2 antibodies (puncorr = 0.03). In patients with no detected antibodies, the DRB1*04-DQA1*03-DQB1*03 haplotype frequency was decreased in PM (16.7%) compared to DM (26.1%).

Table 5

DRB1-DQA1-DQB1 haplotype

%

Controls

PM

DM

Other antibodiesa

Overall

Overall

AS

Mi-2

PM-Scl

U1-RNP

SRP

2n = 284

2n = 220

2n = 208

2n = 98

2n = 36

2n = 22

2n = 24

2n = 12

04-03-03

20.4

16.4

19.1

17.3

13.8

4.5

37.5

0

03-05-02b

16.5

33.6

24.5

43.9

8.3

54.5

12.5

4.1

02-01-06

13.7

9.1

9.6

10.2

8.3

4.5

20.8

25.0

01-01-05

10.6

11.8

13.5

7.1

22.2

9.1

16.7

8.3

13-01-06

10.2

6.4

5.8

6.1

0

4.5

1.0

8.3

07-02-02c

9.2

4.1

13.9

7.1

33.3

18.2

0

0

11-05-03

4.6

7.3

5.3

2.0

5.6

0

0

16.7

07-02-03

3.9

0.4

3.8

0

5.6

0

1.0

0

Estimated haplotype frequencies of HLA class II loci

Examining other antibody associations, the DRB1*03-DQA1*05-DQB1*02 haplotype was also associated with risk for the presence of anti-PM-Scl antibodies, with all 11 anti-PM-Scl positive patients possessing at least one copy. The DRB1*04-DQA1*03-DQB1*03 haplotype frequency was increased in anti-U1-RNP positive patients versus controls (p = NS). Both DRB1*02-DQA1*01-DQB1*06 and DRB1*11-DQA1*05-DQB1*03 haplotypes were increased in anti-SRP positive patients versus controls (p = NS for both).

Interstitial lung disease

There was a strong association of anti-tRNA synthetase positive patients with ILD (OR 9.5, 95% CI 3.9–23.9, p = 2 × 10-09), irrespective of myositis subtype. A strikingobservation was that 21/22 patients with ILD in association with an anti-tRNA synthetase possessed at least one copy of HLA-DRB1*03-DQA1*05-DQB1*02 (haplotype frequency 52.3% disease versus 16.5% controls, OR 5.5, 95% CI 2.6–11.6, pcorr = 1 × 10-05). Of the remaining ILD group with a detected antibody, four possessed anti-PM-Scl and one possessed anti-SRP antibodies.

As HLA-DQB1*02 could be shared between the HLA-DRB1*03-DQA1*05-DQB1*02 and DRB1*07-DQA1*02-DQB1*02 haplotypes, we examined patients with both haplotypes. Twelve patients possessed HLA-DRB1*03/*07, DQA1*05/*02 and at least one copy of DQB1*02; 50% of these patients also had ILD. Of all the patients with the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype, however, none had ILD unless DRB1*03 and DQA1*05 were also present. Possessing both haplotypes was negatively associated with development of anti-Mi-2 antibodies, and no such patients possessed ILD either. Of note, three anti-Mi-2 positive patients possessed a copy of HLA-DRB1*03 and DQA1*05, a finding that has not previously been described.

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Discussion

The results from this study confirm the previously reported influence of HLA class II associations in governing PM/DM disease susceptibility in Caucasians [4,5,22]. However, the current results also demonstrateimportant differences between PM and DM, in the relative strengths of their HLA class II associations, and in their contrasting associations with HLA-DRB1*07 and DQA1*02. Furthermore, the observed haplotypes appear to influence clinical features in PM/DM, including the presence or absence of ILD, and the pattern of circulating MSAs/MAAs detected. Thus, HLA class II associations appear to not only govern disease susceptibility in PM and DM, but also to govern the expression of certain phenotypic features common to both myositis subtypes.

The PM/DM subtype differences detected may be partlyexplained by their differing serological associations. Thus, HLA-DRB1*07 and DQA1*02 are risk factors for DM and anti-Mi-2 antibodies, whereas anti-Mi-2 is rare in PM, where these alleles are protective. However, HLA-DRB1*07 and DQA1*02 stilldiscriminate between PM and DM even after allowing for the presence of anti-Mi-2 antibodies. In PM, it is possible that the high DRB1*03-DQA1*05-DQB1*02 frequency may be responsible for lowering the DRB1*07-DQA1*02-DQB1*02 frequency, due to the shared DQB1*02 allele. Indeed, in DM, HLA-DQB1*02 had the strongest effect because of the increased frequency of both haplotypes. The DRB1*03-DQA1*05-DQB1*02 haplotype is associated with anti-tRNA synthetases, and the development of ILD in patients of both myositis subtypes. The negative associations of HLA-DRB1*07-DQA1*02-DQB1*02 and anti-Mi-2 antibodies with ILD suggest a genetically determined patient cohort with a favourableoutcome. The strong associations of DRB1*03-DQA1*05-DQB1*02 with anti-synthetases and ILD suggest a genetically determined patient cohort with an unfavourable outcome.

The relative prevalence of dermatomyositis and polymyositis in Europe exhibits a latitudinal gradient

GJ Hengstman et. al

Ann Rheum Dis, 2000

Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians: ethnogeographic influences in the genetics and clinical expression of myositis

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